Access valve devices, their use in separation apparatus, and corresponding methods

ABSTRACT

An access valve suitable for controlling fluid flow into and out of a chromatography column has a central axially movable probe with a head acting as a spool valve in a barrel. Axial movement of the probe adjusts the valve between a fully open condition, in which bota first conduit extending through the probe and a second conduit defined around the probe are open to the column interior, a partly open condition in which a second sealing land on the probe closes the second conduit, and a fully closed position in which both conduits are closed. The three positions are useful for packing and unpacking chromatography media into and from the column. In the closed condition of the valve, the first and second conduits communicate with one another so that the valve interior can be cleaned while the column is operating.

This application is a Divisional of U.S. patent application Ser. No.09/495,359 filed on Feb. 1, 2000, now U.S. Pat. No. 6,277,283 which is aDivisional of U.S. patent application Ser. No. 09/157,585, filed Sep.21,1998, now U.S. Pat. No. 6,090,279, which is a Divisional of U.S.patent application Ser. No. 08/825,026, filed Mar. 26, 1997, now U.S.Pat. No. 5,902,485, which is a continuation of PCT/GB95/02338 having aninternational filing date of Oct. 3, 1995. PCT Patent Application No.PCT/GB95/02338 is incorporated herein by reference.

FIELD OF THE INVENTION

This specification relates to methods and apparatus for the control offluid flow, e.g in chromatography, i.e. apparatus and methods forseparating substances by passing a mobile phase through a stationary orretained phase to cause separation of mobile phase components.

BACKGROUND

Chromatography is a well-established and valuable technique in bothpreparative and analytical work as well as in purification generally.Typical industrial chromatography apparatus has an upright housing inwhich a bed of packing material, usually particulate, rests against apermeable retaining layer. Fluid mobile phase enters through an inlete.g at the top of the column, usually through a porous, perforated, meshor other restricted-permeability layer, moves through the packing bedand is taken out at an outlet, typically below a restricted-permeabilitylayer.

Changing the bed of packing material, because it is spent or in order torun a different process, is an arduous task particularly with bigindustrial columns which can be hundreds of liters in volume. Theexisting bed has usually become compacted and difficult to remove. Thehousing must be dismantled, the compacted packing mass disrupted andthen removed. Furthermore, the new bed must be very evenly packed if thecolumn is to be effective: the fresh material must be added carefullywhile maintaining a flow of liquid. Usually the apparatus must be keptclean, particularly with biological products where high system sterilitymay be needed for weeks or even months. One small contamination can bedisastrous.

Conventionally, many hours have been needed to change the spent packingin a big column.

GB-A-2258415 describes a column which can be packed and unpacked withouttaking it apart, using special supply and discharge valves in the topand bottom plates of the housing. The packing supply valve has a spraynozzle which can be retracted into the top plate, with the sprayopenings closed by a seal on the plate, or advanced to project into thecolumn bed space, freeing the openings for a slurry of packing materialto be pumped in. The discharge valve has an advanceable nozzle withradially-directed spray openings at its enlarged head, positionedcoaxially within a wider bore of the bottom plate. When retracted, thehead fits in the bore to seal itself and the bore. To empty the column,the nozzle is advanced and buffer liquid pumped through it. The advancednozzle head breaks up the packed medium and the pumped-in buffer carriesit out through the larger bore, now opened.

There are difficulties in maintaining long-term sanitary conditions withthese valve assemblies.

THE INVENTION

We now propose further developments.

In one aspect we provide separation apparatus having a column housingwhose housing wall defines an enclosed bed space which in use contains abed of packing material. The housing wall includes end walls at oppositeends (in terms of an operational fluid flow direction) of the bed spaceand having inlet and outlet openings for fluid communication to and fromthe bed space in use. An access valve device communicates with the bedspace through the housing wall at an access location. This valve devicehas first and second adjacent fluid-flow conduits, each having anexterior connection and an interior opening adjacent the housing wallinterior. The valve device is controllably adjustable, from outside thehousing wall, between

a first, closed condition in which the first and second conduits areboth isolated from the bed space;

a second, partially-open condition in which the device puts the firstconduit in communication with the bed space but isolates the secondconduit from the bed space, and

a third, open condition in which the device puts the first and secondconduits both in communication with the bed space.

An access valve of this type offers a number of possible operationaladvantages. Some are described later. One feature it can offer ispacking and unpacking a bed space through a single housing wallinstallation. The relevant processes may be as follows.

To unpack, the valve is moved to the third condition in which both thefirst and second conduits are open to the bed space. Fluid is forced inthrough the first conduit to disrupt and disperse the packed bed, theflowable dispersion of the packing material then flowing out through thesecond conduit.

Preferred features for these purposes include the following.

The opening of the first conduit may have a spray nozzle or otherrestriction, fixed or adjustable, to help disrupt the bed by flowvelocity. Having plural outlet openings also helps to reach a largerregion of the bed space and clear it more effectively.

The access valve device preferably comprises a probe which, from aretracted condition recessed into the housing wall, can be advanced intothe bed space to disrupt material therein. The disrupting probe ispreferably a movable valve element defining one or both of the conduits,preferably the first conduit at its outlet (which may be at or throughthe head of the probe e.g. as in GB-A-2258415).

The opening of the second conduit may form an outlet from the bed space.Desirably it is a single aperture. Desirably it has cross-sectional areaat least a substantial proportion of the cross-sectional flow areawithin the second conduit itself. Desirably the cross-sectional area ofthe second conduit through the valve device is generally larger thanthat of the first conduit.

To pack, the access valve device can be adjusted to the second,partially-open condition and packing material forced in through thefirst conduit, typically as a dispersion of particles in carrier fluid.Carrier fluid escapes from the bed space through an outlet remote fromthe valve device, while packing material is retained.

Thus, a bed of new packing material can be packed against a permeableend retainer at a housing wall location spaced from and preferablyopposed to that of the valve device, by maintaining a flow of carrierfluid through the accumulating bed and out through the end retainer.This flow of carrier fluid can accompany the injection of bed materialthrough the first conduit.

The valve device preferably has relatively movable valve parts orelements which are movable in or into face-to-face sealing contact withone another, and defining the first and second conduits. A pair of suchelements may be sufficient to define the first and second conduits andalso sealing portions or lands sufficient for shutting off their inwardopenings for the three conditions mentioned above. Respective spacedsealing portions on one part or element can sealingly engage a singlesealing portion, or plural differently-spaced sealing portions, on theother relatively movable part or element to provide the first and secondconditions.

The relative movement between the valve elements passing between thethree conditions may be linear (typically in the direction through thehousing wall, preferably perpendicularly), rotational (typically arounda direction axis as specified above) or a combination of these e.g.moved linearly by a screw thread action. The three conditions desirablycorrespond to three spaced stations along a predetermined singlerotational, linear or combination (e.g. helical) path or track for suchrelative movement.

For simplicity one such valve element may have a single sealing landwhich in the closed condition isolates the first conduit from the bedspace and in the partially-open condition isolates the second conduitfrom the bed space. This land may be on a said valve element fixedrelative to the housing wall, provided at or adjacent a mouth of thevalve device. The openings of the first and second conduits can then bedefined by one or more further valve elements which is/are slidablymoveable relative to that sealing land.

Valves as proposed above are also usable to govern flow into/out of anyvessel or conduit; not only separation apparatus housings.

It is a particularly desirable feature for a component of a separatorapparatus, and also in other contexts, that it be cleanable in place(“CIP”) i.e. without removing it from the apparatus and most preferablywithout interfering with the bed space e.g. while separation is inprogress.

In a further aspect we propose that this be achievable, in an accessvalve device governing the communication of first and second conduitsthrough the housing wall of a separator apparatus bed space asdescribed, or through the well of any vessel or conduit into a space, byarranging that in a closed condition of the valve in which both firstand second conduits are isolated from the space a continuous cleaningpath is defined along the first conduit, through e.g. a cleaning recessin the valve device connecting between the first and second conduits,and along the second conduit. The valve device components are shapedsuch that, for cleaning fluid flow in at least one direction along thecleaning path, all regions thereof are swept i.e. there are no deadspaces. In particular, for at least one said flow direction at no pointin the valve device does the surface of the first conduit, secondconduit or the connecting recess diverge from or converge towards thecentral flow axis (or layer, according to the flow path shape) at aright-angle or greater, and preferably not at an angle greater than 70°.

One particular proposal provides the possibility of such a flow path ina three-condition valve device as proposed above, having relativelymovable valve elements, one of the elements having an isolating sealwhich seals in the first condition against a first opposed sealingsurface of the other element and in the second condition seals against asecond opposed sealing surface of the other element, isolating the firstand second conduits respectively from the bed space. According to ourproposal the one valve element defines a recess behind its isolatingseal which, in the closed condition, provides clearance around thesecond sealing surface of the other element to put the first and secondfluid conduits in communication with one another.

In separation apparatus, a preferred location for an access valve in anyof the aspects described above is in an end wall construction of thehousing. This end wall is typically fluid-permeable but impermeable tothe relevant packing material, e.g. by virtue of a porous, perforated ormesh layer—a filter layer. The access valve openings open to the bedspace side of this layer. Generally further openings are provided forintroducing fluid material, e.g. a sample or mobile phase generally,behind that filter layer e.g. along a third conduit which extendsthrough the end wall alongside the valve device.

Another aspect provides uses of an access valve device as described forremoving material from a column bed space, and in an additional versionthis may be part of a separation process.

The additional version relates to a separation process in which a liquidincorporating components to be separated is caused to flow upwardlythrough a bed of particulate stationary phase (packing medium) enclosedin a bed space of a column housing, for example at a rate which expandsor fluidises the bed. After passing through the bed the liquid passes arestricted-permeability element (typically a mesh, or a porous or otherperforated layer which will retain the packing medium particles) and outof the column housing through a process outlet.

The liquid may incorporate particulate or cohesive matter which will notpass, or not freely pass, the restricted-permeability element.Biological culture products are an important example of this. Forinstance, expanded bed separation is used to remove a target protein, byadsorption onto the bed particles, from an unclarified orpartially-clarified culture broth containing cells, cell debris, lipidparticles and/or the like.

As separation proceeds, such materials accumulate against therestricted-permeability element used to prevent escape of packingmaterial through the process outlet. In time, the accumulated matterprevents effective operation. Processing must be stopped, the columnhousing opened and the accumulated matter cleared before restarting.

Our proposal is to remove such accumulated matter from the bed space,e.g. from time to time as the process proceeds, and optionally withoutcutting off the input of feed stock liquid, by

opening a clearing outlet for accumulated matter at a location at oradjacent the restricted-permeability element and communicating directlywith the bed space, and

forcing a clearing flow of fluid at, across and/or back through therestricted-permeability element to disturb the accumulated matter sothat it passes out through the clearing outlet.

So, the separation process may continue with reduced or eliminatedinterruptions for clearance of accumulated matter from the bed space.

The clearing flow may be provided by forcing a reverse flow through therestricted-permeability element, e.g. back through the process outlet,or through other conduits penetrating the impermeable wall behind therestricted-permeability element. Additionally or alternatively theclearing flow may come through one or more nozzles on the bed space sideof the element by pumping fluid out of them e.g. at the centre of theelement, and desirably with a clearing flow radiating from a conduitpenetrating the housing wall.

These functions may be served by an access valve device as disclosed inthe previous aspects above.

Another proposal in the context of such a process involves theintroduction of a mobile phase into the column bed space through adirect input opening, preferably valve-governed, rather than through arestricted-permeability element which is provided to retain the inletside of the packing bed. For example, introduction is through an accessvalve device opening through the restricted-permeability element.

In this way a mobile phase incorporating particulate matter, or othermatter which might clog the restricted-permeability element, can beintroduced conveniently into the bed for processing. The access valvedevice used for the introduction may be e.g. any as described above.

By combining this proposal with the previous one, the introducedparticulate or other matter can then conveniently be cleared from thebed space.

A further aspect provided herein is a valve device for governing flowthrough a housing or conduit wall into a space, e.g for a chromatographycolumn housing wall. The valve device has an outer barrel elementdefining an axial direction. The barrel has an internal bore extendingaxially from an outer end to an inner end of the barrel, withaxially-directed openings at both ends. The opening at the inner endconstitutes a valve mouth, and provides a radially-inwardly directedmouth sealing surface of the bore.

An elongate spool element extends axially through the barrel bore and isaxially movable relative to it. A central fluid conduit extends axiallythrough the spool element, and opens adjacent the barrel mouthpreferably by plural radially-directed openings, preferably as a spraynozzle. The spool element has a first, inner radially-outwardly directedsealing land disposed axially inwardly of the central conduit openingand adapted to seal against the barrel's mouth sealing surface in afirst relative longitudinal position of the spool element relative tothe barrel, thereby isolating the central conduit opening from the valvemouth.

The spool element also has a second, outer radially-outwardly directedsealing land disposed axially outwardly of the central conduit openingand adapted to seal against the barrel's mouth sealing surface in asecond, intermediate longitudinal position of the spool element relativeto the barrel in which the central conduit opening is exposed to theinterior space. Outwardly of the second sealing land is a spacing,preferably annular, between the spool element and the barrel bore. Thisspacing constitutes an outer axially-extending fluid conduit which in asecond, intermediate position is isolated from the valve mouth by thesealing of the second land.

In a third, inward position of the spool element relative to the barrelthe second sealing land is clear of the mouth sealing surface and boththe inner and outer conduits are open to the interior.

This valve device is suitable for use in all of the above aspects.

The barrel bore may have a recess disposed outwardly of the mouthsealing surface and connecting the inner conduit opening to the outerconduit in the fully-closed position.

The valve may be installed in the wall with the valve mouth at the wallinterior and at the wall exterior a connecting manifold providing afixed communicating connection to the outer conduit at the outer end ofthe barrel and a movable communicating connection to the inner conduitof the spool element. Means for driving controllable movement of thespool element is also provided. This may take various forms which askilled person can provide without difficulty. For example, as disclosedin GB-A-2258415 the spool element may be thread-mounted into themanifold or another fixed component, the drive means functioning torotate it to a controlled extent to give the desired axial shift.

In separation apparatus the valve may be installed in an end wall havingan inner restricted-permeability layer and an outer impermeable walllayer, the valve mouth communicating through the restricted-permeabilitylayer. The outside of the barrel at the mouth may overlap therestricted-permeability layer to trap it. To introduce process fluidsinto the bed space, one or more process conduits lead through theimpermeable wall layer to behind the restricted-permeability layer, e.g.alongside the valve barrel as one or more clearances between the valvebarrel and the surrounding impermeable layer of the end wall.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of our proposal are now described in detail, with referenceto the accompanying drawings in which

FIG. 1 is a cross-sectional schematic side view of a chromatographycolumn showing the basic features thereof;

FIG. 2 is an axial cross-section showing an end plate construction inmore detail;

FIG. 3 shows enlarged, in axial cross-section, the construction of anaccess valve;

FIG. 4 is an axial cross-section corresponding to FIG. 2 with the accessvalve in a part-open position;

FIG. 5 is an axial cross-section corresponding to FIG. 2 but with theaccess valve in a fully-open position;

FIG. 6 is an axial cross-section of the end plate illustrating a mediumpacking operation;

FIG. 7 is a view corresponding to FIG. 6, with the column in operationand the access valve being cleaned;

FIG. 8 is an axial cross-section corresponding to FIG. 6 illustratingthe process of unpacking a packing medium from the column;

FIG. 9 is an axial cross-section of the top end plate of achromatography column undergoing expanded-bed chromatography,illustrating a clearing operation;

FIG. 10 is an axial cross-section of a column end which is a variant ofthat in FIGS. 2 to 8; and

FIG. 11 is a schematic view of a second version of the access valve.

DETAILED DESCRIPTION OF EMBODIMENTS

FIG. 1 shows schematically the general components of a chromatographycolumn 1. The column has a cylindrical fluid-impermeable side wall 11,e.g. of stainless steel or a high-strength/reinforced polymeric materialwhich may be translucent. The open top and bottom ends of the side wall11 are closed by top and bottom end assemblies 12,13. Each end assemblyhas a fluid-impermeable end plate 3 fitting sealingly to plug theopening of the cylindrical wall 11, and preferably of stainless steel orhigh-strength engineering plastics material, e.g polypropylene. The endplates are backed up by metal retaining plates 2 bearing against theirouter surfaces and projecting radially beyond the side wall as retainingflanges 22 through which adjustable tension rods 14 are secured. Theselink the top and end assemblies 12,13 and help the construction towithstand high fluid pressures.

Each end plate 3 has a central through-opening 31 for communicationbetween the exterior of the column and the packing bed space 9 definedby the side wall 11 and end assemblies 12, 13. Access through theopening 31 is subdivided into separate conduits, connected externallythrough a connection manifold 8.

A filter layer 4, typically of filtered or woven plastics or steel,extends across the area of the bed space 9 at the inner surface of theend plate 3. The inner surface 35 of the end plate 3 is recessed behindthe filter layer 4, e.g. conically as illustrated, and preferably withthe use of support ribs (not indicated) supporting the filter layer 4from behind, to define between them a filtration space 34. One of thecommunication conduits, a mobile phase conduit 33, opens inwardly intothis filtration space 34, as well as outwardly to a mobile phaseconnector 81 of the manifold 8.

From the manifold 8, an access valve device 5 projects inwardly throughthe end plate opening 31 and sealingly through a central orifice 41 ofthe filter layer 4. The access valve 5, embodiments of which aredescribed in more detail below, governs the communication of one or moreconduits from the manifold 8 directly to the bed space 9, i.e. bypassingthe filter layer 4. Indicated here are first and second valved conduits51, 61 governed by the valve 5, and connected externally throughconnectors 82 of the manifold 8.

In a typical operation of the column, a packed bed of particulatestationary phase material fills the bed space 9 between the top andbottom filter layers 4. The valve devices 5 being closed, a mobile phaseis fed in through mobile phase connector 81 (arrow “A”), passes throughconduit 33 into the filtration space 34 and through the filter layer 4to elute down through the packed bed, effecting separation of itscomponents. Liquid eluate passes thought the filter layer 4 of thebottom end assembly 13 and out through the mobile phase connector 81thereof (arrow “B”) for collection as appropriate.

FIG. 1 and the above explanation are to illustrate general relationshipsof components and a typical mode of operation. The skilled person knows,and it will also appear from the following description, that otherspecific constructions and modes of operation may be appropriate fordifferent kinds of process.

A more detailed embodiment of an end plate and valve construction is nowdescribed with reference to FIGS. 2 and 3.

A manifold 8 is provided as a machined metal or plastics block fixedsealingly over the central opening 31 of the end plate 3 by threadedconnectors 88, and recessed into a central aperture 23 of an outer metalretaining plate 2 which is fixed to the end plate 3 by bolts 21 or othersuitable fasteners. The periphery of the end plate 3 seals against thecolumn side wall 11 with an annular polymeric seal member 32 which alsooverlaps the filter layer 4 to retain its periphery. This seal membermay have an internal rigid reinforcement. Unlike a conventional O-ringit eliminates dead space by sealing with a cylindrical surface andmounting in a shape-fitting groove of the end plate.

The manifold 8 has a central bore 91 coaxial with the plate opening 31and having inwardly and outwardly directed threaded connection openings83, 89. The cylindrical barrel 6 of a spool valve 5 is screwed into theinward connection 83, to extend coaxially inwardly through the centralplate opening 31 and out through a central circular orifice 41 of thefilter layer 4, terminating in an outward flange 65 which overlaps thefilter layer 4. A cylindrical outer sleeve 66 fits snugly around thebarrel 6, its outward edge resting against the inward face of themanifold block through a polymeric sealing ring 662 and its inner edgeresting against the outer surface of the filter layer 4 through anotherpolymeric sealing ring 661, trapping the layer 4 between the sleeve 66and barrel flange 65. Since the barrel's outer diameter corresponds tothat of the layer orifice 41, it is possible in the illustratedcondition to remove the barrel by unscrewing it and withdrawing itinwardly, without disturbing the filter layer 4. This is an advantagefor column maintenance.

One or more flow conduits 33 are created by clearance between the barrelassembly (barrel and sleeve) and the plate opening 31. Thus, the plateopening 31 may have a plurality of axially-extending channelsdistributed around it to form the conduits 33, intervening surfaces ofthe opening 31 fitting against the barrel assembly. Or, a full annularclearance may be provided. Or, these conduits may be provided away fromthe barrel assembly, defined only through the material of the plate 3.The inner ends of the conduits 33 communicate into the filtration space34. Their outer ends align sealingly (by virtue of polymeric sealingrings 662,663) with connection conduits 811 of the manifold block,connected in common to a threaded or otherwise connectable port 81. Thisestablishes direct fluid communication between filtration space 34 andthe port 81, while communication between the bed space 9 and port 81 isnecessarily through the filter layer 4. Ribs provided on the inner platesurface 35 (in known manner) assist even distribution or collection offluid to or from the space 34.

A bore 61 extends axially through the barrel 6 from one end to theother. The bore's outward end merges sealingly (by polymeric sealingring 664) and without change of diameter into the central manifold bore91. The inward end of the bore 6 is on the bed space side of the filterlayer 4, and constitutes a mouth opening 611. The bore 61 has a uniformcylindrical cross-section except for a radially-enlarged portion nearbut outward of the mouth 611. The enlarged portion 612 has a centralcylindrical part bordered on either side by tapering surfaces 613. Theseare angled at not more than 450 from axial.

A central probe element 7 acts in the bore 61, to give the function of aspool valve. The probe element 7 has an elongate tube 72 with an openinternal bore 73, extending axially from adjacent the barrel mouth 611out through the outward end of the barrel 6 and the coaxial ball 91 ofthe manifold 8. Outwardly of the outer barrel end, a tapered sealingring 665 seals between the tube 72 and surrounding manifold ball 91: aplug collar 87 is screwed into the outer connection 89 of the manifoldto hold the tapered seal 665 effectively in place.

At its inward end, the probe 7 has a solid head 71 with a pointed tip74, terminating the bore 73. The head 71 has a cylindrical sealingsurface 711, of the same diameter as the barrel bore 61, and which asshown can seal against an inward sealing surface 64 at the mouth 611 ofthe barrel bore 61, assisted by a flush-recessed polymeric sealing ring641.

The probe bore 73 opens at a set (FIG. 4) of spray openings 75 openingthrough and distributed circumferentially around the tube 72. The tipsealing surface 711 stands radially proud of these openings 75.Immediately outwardly of the openings the probe head 71 has anotherradially-enlarged portion or land 76 which presents a cylindricalsealing surface 761 bordered by tapering portions 762 angled at not morethan 45° from the axial.

Outwardly of this second enlargement 76 the tube exterior 72 is a plaincylinder.

The diameter of the sealing surface 761 on the second enlargement 76 isthe same as that 711 on the first enlargement 71.

The tube 72 being narrower than the barrel ball 61, an annular-sectionclearance 51 is defined between them. This constitutes an outer valveconduit extending out through the outer end of the barrel 6 into themanifold bore 91 up to the seal 665, where it diverts to a threaded orotherwise connectable manifold port 82.

Beyond the manifold 8, the outer end of the probe tube 72 is connectedto means for advancing or retracting it axially relative to the barrel6, with sliding through the seal 665. These means may be motor or servoactivated, e.g. advancing the probe 7 by rotating a fixed drive memberwhich engages the tube 72 via a screw thread, e.g. as proposed inGB-A-2258415. Additionally or alternatively, a manual control isprovided for the axial adjustment.

The spool valve effect of the valve 5 is as follows.

FIGS. 2 and 3 show a first, closed condition in which the head sealingland 711 seals with the mouth sealing surface 64 of the barrel,isolating both the valve conduits 51, 73 from the bed space 9. Thefiltration conduits 33 are not affected by the valve. The nozzleopenings 75 and the second sealing land 76 register axially with theradially-enlarged portion 612 of the barrel bore 61. This puts thenozzle openings 75 into communication with the outer valve conduit 51,creating a continuous sealingly-enclosed flow path between the probetube bore 73 and the manifold port 82. This path has no unswept areas ordead spaces. Within the valve device 5, none of its boundary surfacesdeviates from the local central flow axis/layer by more than 45°,assisting effective sweeping. In the manifold the path likewise has nodead ends.

Consequently, when the chromatography column is running (see also FIG.7) the valve device and its associated connections can be cleaned inplace by feeding a cleaning solution (e.g. aqueous alkali, or othersuitable cleaning medium known to the art) through that fully-sweepablecleaning path. It is particularly envisaged to feed the cleaningsolution in through the probe tube 72.

FIG. 4 illustrates a second, partially-open condition of the valve 5.The probe tube 72 is advanced sufficiently to bring the second sealingland 76 into register with the bore mouth 611, where their respectivesealing surfaces 761, 64 effect a sliding seal. This also brings thenozzle openings 75 to outside the mouth 611, communicating with the bedspace 9. Accordingly the inner valve conduit constituted by the bore 73is put into direct communication with the bed space, bypassing thefilter layer 4, while the outer valve conduit 51 remains isolated fromthe bed space 9.

FIG. 6 illustrates an application of this in creating a new bed ofpacking material. The packing itself can be as described inGB-A-2258415. Specifically a flowable flurry of packing materialparticles in carrier liquid is pumped in through the tube 72 and spraysout radially in circumferentially-distributed directions from theopenings 75. As packing material accumulates in the bed space 9 excesscarrier fluid escapes through the filter layer 4 and away through thefiltration conduits 33 and manifold port 81, to which a connecting tubeis fastened. This is continued until sufficient packing material hasbeen introduced.

FIG. 5 illustrates a third condition of the valve. Here the probe tube72 has been advanced further inwardly to bring the second sealing land76 clear of the mouth seal 64, which now opposes the smaller-diameterouter surface of the tube 72 to create a clearance, opening the outervalve conduit 51 to the bed space 9 through the mouth 611.

FIG. 8 shows how to exploit this third condition to unpack material froma column bed. It should be noted that, as disclosed in GB-A-2258415, theadvanced pointed head 71 of the probe 7 is apt to disrupt existing bedmaterial, which is often a hard compacted mass, and thereby help toinitiate unpacking. A carrier liquid such as a buffer is pumped inthrough the probe bore 73 and out through the nozzle openings 75; itshigh nozzle velocity helps to disrupt and entrain the packed material.The particulate packing material cannot pass the filter layer 4, but itcan respond to the pumping in of liquid by escaping as a slurry throughthe mouth 611 of the valve and along the outer valve conduit 51 to themanifold port 82 for discharge along a connected tube.

So, for the first time a single column wall installation enables bothpacking and unpacking of a column. This can give much greaterflexibility in column operation. Note that the packing and unpackingoperations can be effected entirely from outside the column housing,without needing to dismantle or remove the end assemblies. Furthermorethe valve which can do this can itself be cleaned in place, even whenthe column is running by introducing a mobile phase onto the bed throughthe filtration conduits 33 as shown in FIG. 7. So, even this relativelysophisticated wall installation does not introduce a risk ofcontaminants accumulating and leaching into a long-running processperhaps with disastrous results. In the terminology of the skilledperson in this field, this valve device is a “sanitary” installation.

Furthermore the valve is easily dismantled for maintenance because theprobe 7 can be entirely withdrawn inwardly from the barrel bore 61.

Further modes of use, in relation to expanded-bed separation processes,are explained with reference to FIGS. 9 and 10. Expanded bed adsorptionis a recently-developed separation technique, particularly for reducingor eliminating the need to clarify biological cultures before elutingthem through a packing to separate out a desired component. The packingbed is expanded by an upflow of liquid medium so that even particulatematerial in the sample can work its way through the bed to the outletabove the bed. For expansion the bed must rest on a permeable layerthrough which the liquid up-flow is established. Introduction of thesample must therefore generally be done as a single pass, which samplebatch then elutes through the bed. Usually desired materials areadsorbed onto the bed particles, and in a subsequent step are recoveredby stopping the liquid up-flow, compressing the bed by moving down theupper plate and then percolating through the bed a liquid that desorbsthe target substance from the bed particles.

A column for this can have top and bottom retaining assemblies whicheach have an impermeable plate interior filter layer and a central valvedevice as shown in the previous Figures. The normal filtration conduitsand means for establishing up-flow of a mobile phase are also provided.

A first feature here is that a sample e.g. unclarified broth, canconveniently be introduced into the expanded bed, bypassing the lowerfilter mesh, by injecting it though the inner valve conduit 73 of thelower valve in its second, partially open condition. Where sample isinjected intermittently the lower valve is returned to its fully-closedfirst condition in between. Our new valve construction thereforeprovides a convenient way of introducing such a sample past a meshrequired for maintaining an up-flow.

A second and very significant feature is explained in relation to FIG.9, which shows in more detail a top end assembly for the expanded-bedprocess.

During normal running of the process the mobile phase passes through thefilter layer 4′, through the filtration conduits 33′ and out. There is agradual accumulation of particulate debris and other matter reluctant topass the filter 4, e.g. lipids. This therefore accumulates in an upperbed space region 91 adjacent to filter layer 4. In time it hinders themaintenance of proper flow.

By moving the upper valve device 5′ to its third, fully-open conditionfor a short period of time, while creating a clearing flow of liquidadjacent the filter layer 4′ to disturb the accumulated matter, thismatter can be caused to follow the clearing flow out of the bed spacevia the outer valve conduit 51. One method of achieving a clearing flowis to provide a short blast of suitable liquid, e.g. a buffer, throughthe probe bore 73′ and out through the nozzle openings 75′ which arenear the filter layer 4′. Alternatively or additionally, the normal flowdirection (arrow “X”) of buffer out of the system can temporarily bereversed and buffer pumped back in through the filtration conduits 33′(arrow “Y”), thereby creating a temporarily downward flow through thefilter layer 41 (arrow “Z”), disrupting the accumulated material so thatit can accompany the escape of the temporary liquid pressure wave outthrough the valve conduit 51. This may be done either with or withoutcutoff of the supply of sample at the bottom of the column.

Thus, the process can be run as long as the absorption proceedsefficiently, without needing to stop for other reasons. This is a highlyadvantageous procedure.

FIG. 10 shows a variant end plate construction for a chromatographycolumn. The differences from the previous embodiment include thefollowing.

The filter layer 4 is formed integrally with inner and outer annuli41,42, in one piece in plastics material.

The inner annulus 41 forms a flush termination for the barrel 6 of thecentral valve 5, and has an inwardly-facing surface to form the sealwith the valve's central probe. This flush one-piece constructionfurther reduces the risk of contamination at the point of access. Italso enables the filter layer's inner periphery to self-trap in a grooveof the valve barrel 6, enabling that barrel 6 to be one component ratherthan two. The end cell and valve components may be of polypropylene.

The filter layer's outer annulus 42 is used to hold the filter layer inplace by trapping between the wall 11 of the column and the end plate 3of the cell, which in this version is a one-piece polypropyleneconstruction.

The connection manifold 8 has the mobile phase inlet/outlet port 81 andthe waste slurry outlet port 82 inclined outwardly, rather thanperpendicularly as in the previous embodiment, to improve flow. Afurther significant feature in this embodiment is that the filter layer4 is concave, by virtue of the support ribs on the end plate 3 beingformed with inclined rather than slightly radial edges. We find thatthis slight conicity improves drainage from the column during clearing.

FIG. 11 shows schematically a different embodiment valve which howeverembodies similar concepts. Here the central movable probe is a simplearmature rather than a fluid-carrying nozzle. Its enlarged head 171 iscarried on actuating rod 272 and has a flat end surface 1712, a firstouter sealing land 1711, a conical convergence 1613 to a narrow recessor waist 1612, and a smaller enlargement 176 with a second sealingsurface 1761.

The mobile phase conduit 33 is provide outside the valve barrel 6 asbefore. Inside the valve barrel the central fluid conduit 173 is definednot through the probe 272,171 but rather by an inner conduit wall 172surrounding the probe shaft 272 and having an opening with aninwardly-directed seal 174, recessed back from the main opening throughthe filter layer 4, which has its own inwardly-directed seal 141 at themouth of the outer conduit defined between the outer barrel wall 6 andthe inner conduit wall 172.

FIG. 11 shows the valve fully open, with the central probe fullyadvanced to open both conduits e.g for unpacking and column. Unpackingliquid is pumped in through the inner conduit 173 and squirts out aroundthe armature head 171; waste slurry flows back and out through the outerconduit.

In the partially open position, e.g for packing a column, the armatureis partially retracted so that second sealing surface 1761 seals off theinner conduit, the outer conduit remaining open. Slurry can be pumped inthrough the outer conduit. This shears the slurry less than the spraynozzle of the first embodiment.

Full retraction of the armature brings its front surface 1712 flush withthe filter layer 4 and its first head sealing surface 1711 into sealingengagement with the central filter opening seal 141, closing off theouter conduit. At the same time the second sealing land 176 drops belowthe inner conduit seal 174 which then opposes the recess 1612 to permita circulating, clean-in-place flow through the inner and outer conduits.

Note that in the open conditions the conical portion 1613 of the head171 can be axially adjusted to alter the direction of liquid pumped in.This embodiment illustrates how two separate seals on the fixed part ofthe valve can provide the same effect as previously if their spacing isdifferent from that of the corresponding sealing portions of the movablepart.

What is claimed is:
 1. A separation process for separating a targetcomponent from a liquid incorporating the target component with one ormore other components, the separation process comprising providing a bedof particulate packing medium, said medium being adapted to retain thetarget component and said bed thereof being enclosed in a bed spacedefined by a column housing, said housing having a process outlet and arestricted permeability element between the process outlet and bed spaceto retain the particulate packing medium in the bed space; flowingliquid upwardly through the bed of particulate packing medium, throughthe restricted-permeability element and through the process outlet, toexpand the bed in the bed space and effect separation of the targetcomponent from the liquid through retention by the particulate packingmedium; said one or more other components of the liquid comprisingparticulate matter, said particulate matter accumulating against therestricted-permeability element during the flowing of the liquid, andthe process further comprising opening a clearing outlet communicatingdirectly with the bed space, at or adjacent the restricted-permeabilityelement, and forcing a clearing flow of fluid relative to the restrictedpermeability element to disturb the particulate matter which hasaccumulated against it, and causing said matter to pass out of the bedspace through the clearing outlet.
 2. A separation process as claimed inclaim 1, in which the liquid comprises unclarified orpartially-clarified cell culture broth, and the target component is aprotein product in the culture broth.
 3. A separation process as claimedin claim 1 in which the clearing flow comprises a reverse flow forcedback through the restricted permeability element.
 4. A separationprocess as claimed in claim 3, wherein said reverse flow travels throughsaid process outlet and communicates directly with the bed space bypassing through said restricted permeability element.
 5. A separationprocess as claimed in claim 1 in which a said clearing flow is forcedthrough at least one nozzle at the bed space side of therestricted-permeability element.
 6. A separation process as claimed inclaim 5 in which a said nozzle is on a conduit at the centre of therestricted-permeability outlet, and the clearing flow radiates from thenozzle.
 7. A separation process as claimed in claim 5 wherein theclearing flow includes passing flow through said at least one nozzle andalso through a channel defined by s aid process outlet.
 8. A separationprocess according to claim 1 comprising flowing liquid upwardly throughthe bed of a particulate packing material concurrently with the flow ofthe clearing flow.
 9. A separation process as claimed in claim 1 inwhich the column housing has a housing wall and an access valve isprovided through the housing wall and restricted-permeability element toenable communication of first and second fluid flow conduits directlyinto the bed space, said access valve being adjustable between a closedcondition in which said conduits are isolated from the bed space and anopen condition in which said conduits are open to the bed space; saidaccess valve being adjusted in the process to the open positionwhereupon said second fluid flow conduit provides the clearing outletand a said clearing flow of fluid is introduced through the first fluidflow conduit.
 10. A separation process as claimed in claim 1 in whichthe column housing has an inlet-side restricted-permeability element andsaid flowing comprises pumping liquid medium through the inlet-siderestricted-permeability element to expand the bed, and an inlet-sideaccess valve movable between open and closed conditions is provided tocommunicate directly with the bed space, a material containing saidtarget component being introduced directly into the bed space throughsaid inlet-side access valve in its open condition.
 11. A separationprocess as defined in claim 10 in which said material comprises anunclarified or partially-clarified culture broth, and the targetcomponent is a protein product in the culture broth.
 12. A separationprocess as claimed in claim 10 in which the inlet-side access valveopens at the center of the inlet-side restricted permeability element.